Colorectal cancer incidence in path_MLH1 carriers subjected to different follow-up protocols
Seppala, Toni; Pylvanainen, Kirsi; Evans, Dafydd Gareth; Jarvinen, Heikki;
Renkonen-Sinisalo, Laura; Bernstein, Inge; Holinski-Feder, Elke; Sala, Paola; Lindblom, Annika; Macrae,
Finlay
Published in:
Hereditary cancer in clinical practice
DOI:
10.1186/s13053-017-0078-5
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Seppala, T., Pylvanainen, K., Evans, D. G., Jarvinen, H., Renkonen-Sinisalo, L., Bernstein, I., Holinski-Feder, E., Sala, P., Lindblom, A., Macrae, F., Blanco, I., Sijmons, R., Jeffries, J., Vasen, H., Burn, J., Nakken, S., Hovig, E., Rodland, E. A., Tharmaratnam, K., ... Collaboration Mallorca Grp (2017). Colorectal cancer incidence in path_MLH1 carriers subjected to different follow-up protocols: A Prospective Lynch Syndrome Database report. Hereditary cancer in clinical practice, 15, [18]. https://doi.org/10.1186/s13053-017-0078-5
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R E S E A R C H
Open Access
Colorectal cancer incidence in path_MLH1
carriers subjected to different follow-up
protocols: a Prospective Lynch Syndrome
Database report
Toni Seppälä
1,2*, Kirsi Pylvänäinen
2,3, Dafydd Gareth Evans
4,5, Heikki Järvinen
1,2, Laura Renkonen-Sinisalo
1,6,
Inge Bernstein
7,8, Elke Holinski-Feder
9,10, Paola Sala
11, Annika Lindblom
12, Finlay Macrae
13,14, Ignacio Blanco
15,
Rolf Sijmons
16, Jacqueline Jeffries
17, Hans Vasen
18, John Burn
19, Sigve Nakken
20, Eivind Hovig
20,21,22,
Einar Andreas Rødland
20, Kukatharmini Tharmaratnam
23, Wouter H. de Vos tot Nederveen Cappel
24, James Hill
25,
Juul Wijnen
26, Mark Jenkins
30, Maurizio Genuardi
31, Kate Green
4, Fiona Lalloo
4, Lone Sunde
7,27,28, Miriam Mints
29,
Lucio Bertario
11, Marta Pineda
15, Matilde Navarro
15, Monika Morak
9,10, Ian M. Frayling
17, John-Paul Plazzer
13,
Julian R. Sampson
17, Gabriel Capella
15, Gabriela Möslein
32,33, Jukka-Pekka Mecklin
3,34, Pål Møller
35and in
collaboration with The Mallorca Group
Abstract
Background: We have previously reported a high incidence of colorectal cancer (CRC) in carriers of pathogenic MLH1 variants (path_MLH1) despite follow-up with colonoscopy including polypectomy.
Methods: The cohort included Finnish carriers enrolled in 3-yearly colonoscopy (n = 505; 4625 observation years) and carriers from other countries enrolled in colonoscopy 2-yearly or more frequently (n = 439; 3299 observation years). We examined whether the longer interval between colonoscopies in Finland could explain the high incidence of CRC and whether disease expression correlated with differences in population CRC incidence. Results: Cumulative CRC incidences in carriers ofpath_MLH1 at 70-years of age were 41% for males and 36% for females in the Finnish series and 58% and 55% in the non-Finnish series, respectively (p > 0.05). Mean time from last colonoscopy to CRC was 32.7 months in the Finnish compared to 31.0 months in the non-Finnish (p > 0.05) and was therefore unaffected by the recommended colonoscopy interval. Differences in population incidence of CRC could not explain the lower point estimates for CRC in the Finnish series. Ten-year overall survival after CRC was similar for the Finnish and non-Finnish series (88% and 91%, respectively; p > 0.05).
(Continued on next page)
* Correspondence:toni.seppala@fimnet.fi;toni.t.seppala@hus.fi
1
Department of Surgery, Helsinki University Hospital and University of Helsinki, Post Box 340, 00029 Helsinki, Finland
2Finnish Lynch Syndrome registry, Helsinki University Hospital, Helsinki,
Finland
Full list of author information is available at the end of the article
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Seppälä et al. Hereditary Cancer in Clinical Practice (2017) 15:18
(Continued from previous page)
Conclusions: The hypothesis that the high incidence of CRC inpath_MLH1 carriers was caused by a higher incidence in the Finnish series was not valid. We discuss whether the results were influenced by methodological shortcomings in our study or whether the assumption that a shorter interval between colonoscopies leads to a lower CRC incidence may be wrong. This second possibility is intriguing, because it suggests the dogma that CRC inpath_MLH1 carriers develops from polyps that can be detected at colonoscopy and removed to prevent CRC may be erroneous. In view of the excellent 10-year overall survival in the Finnish and non-Finnish series we remain strong advocates of current surveillance practices for those with LS pending studies that will inform new
recommendations on the best surveillance interval.
Keywords: Lynch syndrome, Hereditary non-polyposis colorectal cancer, Colorectal cancer, Microsatellite instability
Background
Lynch syndrome (LS) is an autosomal dominantly inherited cancer syndrome predisposing to colorectal cancer (CRC) and several extra-colonic malignancies [1]. It is the most common hereditary cause of CRC, accounting for about 3% of the disease. LS is caused by constitutional pathogenic variants of any of four DNA mismatch repair (MMR) genes (MLH1, MSH2, PMS2 and MSH6) or by a deletion in the EPCAM gene which leads to MSH2 inactivation. In muta-tion carriers, a somatic mutamuta-tion affecting the second allele leads to defective MMR activity.
Based on the international Prospective Lynch Syndrome Database (PLSD) we have demonstrated that stringent current screening guidelines do not protect fully against the development of colorectal cancer (CRC) inpath_MMR car-riers. This observation is despite undertaking colonoscopies with polypectomies every 3 years or even more frequently [2]. This finding is in contrast to the declared goal of the guidelines [1] that follow-up by colonoscopy and polypect-omy aims to prevent CRC – an outcome that we expected to be true when issuing these guidelines. Nonetheless, LS patients undergoing surveillance often survive their first can-cer and many develop subsequent cancan-cers, again with a good prognosis, albeit a CRC mortality rate of approximately 10%.
There are many possible reasons why CRC continued to occur in our previously reported series despite follow-up with colonoscopy and polypectomy. These reasons include too great an interval between colonoscopies (Table 1). A high rate of interval CRCs in LS patients having surveillance with screening intervals of over 3 years previously prompted those involved in revising guidelines to recommend shorter surveillance intervals [1, 3–11]. This change was based upon the assumption that a major cause of interval cancers was a fast transition from visible adenomatous polyp to cancer as a consequence of the increased mutation rate associated with MMR deficiency [12]. A 3-year interval between colon-oscopies has been shown to reduce the CRC incidence and mortality in LS in a comparative prospective study [3]. However, previous relevant studies [3–7, 13–18] (summa-rized in Table 2) have provided no definite empirically observed evidence to support what interval between
colonoscopies might best prevent CRC in LS, and how protective such an intervention might be.
Among LS patients in our previous reports from PLSD,path_MLH1 carriers had the highest incidence of CRC despite surveillance colonoscopy, making them the best cohort to examine why CRC continued to occur. The first hypothesis considered was that the large num-ber of carriers reported in PLSD who were from Finland represented a potential confounder. The high overall incidence of CRC observed in path_MLH1 carriers in PLSD might have arisen because Finland, unlike other countries, had not shortened the recommended interval between colonoscopies from the original 3 year interval advocated many years ago.
Here we report whether or not the high CRC incidence in path_MLH1 carriers despite colonoscopy surveillance was caused by a high incidence in Finland and investigate time to CRC cancer since last colonoscopy and overall survival.
Methods
The Prospective Lynch syndrome database
PLSD contains data stored as an Oracle© relational database. Details on data storage and manipulation have been described in detail earlier [2]. Patients who were subject to prospective follow-up including colonoscopy were reported from LS registries in 13 centers in Europe and Australia. In some cases screening for early detec-tion of endometrial and ovarian cancer were also imple-mented. Details on the guidelines followed at each contributing center are given in Table 1.
Study design
The design was a prospective, case-based, open observational study ofpath_MLH1 carriers subjected to colonoscopy com-paring two groups with different recommended intervals be-tween colonoscopies. The prospective observations recorded included follow-up from first prospectively planned and car-ried out colonoscopy onwards. Patients with any cancer prior to, or at the age of first colonoscopy (prevalent cancers) were excluded, as were subjects with less than 1 year of prospect-ive observation. The following observations were used: age at
first colonoscopy, gender, age at last observation, months from last completed colonoscopy to diagnosis of CRC, age at any cancer together with the ICD diagnosis of the cancer, and age at death.
Inclusion criteria
All patients included had been subject to prospective follow-up with colonoscopy because of their increased risk for CRC. All were confirmed carriers of path_MLH1 variants by genetic testing. All path_MLH1 variants were checked against the LOVD database (http://chromium.lovd.nl/LOVD2/colon_cancer/). Please see our previous report for a more detailed description of inclusion criteria [2].
Time between colonoscopies in the different centers
All subjects were offered planned regular surveillance colonoscopy and polyp removal according to the guide-lines followed at each reporting center (Table 1). The
recommended colonoscopy interval in the Finnish na-tional registry protocol was 3 years throughout the study period. From 1997 onwards, all the other centers recom-mended surveillance intervals of 2 years or less. Thus, only observations from 1997 onwards were included in the present study. Each center kept track of their activities through medical files and/or research registries, and all were able to contribute complete reports for all patients included with no missing values. Whilst these methods do not conform to the stringency of a clinical trial they none-theless represent the best that can be achieved by a collab-orative group of highly interested expert clinicians working in diverse health service systems.
Surveillance for extra-colonic cancers
Patients in the contributing centers were informed of general cancer awareness but the surveillance for extra-colonic cancers varied across the centers (Table 1).
Table 1 National surveillance protocols for colorectal and endometrial cancer
Center Series cencored
Colonoscopy Gynecological examination Reference no. and additional details Interval From-to Interval From-to Modalities in
addition to clinical examination Finland 2014 3 years 1985–2014 1 year 1995-2014 EB, ultrasound,
CA12-5
[3,4,8]
Denmark 2014 2 years 1991–2014 2 years 1991-2014 US [9] Germany 2014 1 year 1995–2014 1 year 1995-2014 US [10,17] Italy 2013 1-2 years (1 year
when age > 40 years; adenoma)
1990–2013 2 years
(1 years when age > 35 yrs.)
1990-2013 US, Pap smear [11]
UK (Manchester) 2014 2 years 1994–2014 1 year 1990-2014 Hysteroscopy, US, CA12-5
[6]
Sweden 2014 2 years 1990–2000 1 year 1992-2014 US, CA 12-5. Some patients: EB
[25,26] 18 months 2000–2014
Australia 2014 1 year 1990–2014 1 year 1990-2005 US, EB, CA12-5 https://www.nhmrc.gov.au/ _files_nhmrc/publications/ attachments/cp106_0.pdf https://www.nhmrc.gov.au/ _files_nhmrc/publications/ attachments/cp106_0.pdf 2005-2014 Risk reducing surgery only
Spain 2013 1-2 years (1 year when age > 40 years)
1999–2013 1 year 1999-2013 US Unpublished The Netherlands 2013 2-3 years 1987–1996 1-2 years 1994-2005 US [7]
2 years 1997–2013 1-2 years 2005-2013 US, EB UK (Cardiff) 2013 3 years 1991–1994 1 year 1998-2010 US, CA12-5
(3 or 4 monthly)
Unpublished Colonoscopy 96% compliance with interval.
2 years 1994–2013 Gyn: only 27% of
eligible women had gyn. Cancer screening. Since 2010 not systematic. UK (Newcastle) 2014 2 years 1995–2014 No fixed Unpublished
Norway 2013 3 years 1989–1996 2 years 1989-2013 US, CA12-5 [5] 2 years (one year when adenoma) 1996–2013
US Transvaginal ultrasound EB Endometrial biopsy
Cancer treatment
All cancers were treated according to local standards. Treatment modalities were not considered.
Events scored
All infiltrating CRCs were scored using the first three positions in the ICD-9 system. Age at each cancer was recorded. Age at death was recorded.
Annual and cumulative incidence rates
Each patient was observed from age at inclusion to age at last observation or first cancer. For each patient, the number of years observed in each five-year group from 25 years of age onwards was counted. All first cancers were scored according to the age at diagnosis. Annual incidence rates (AIR) for age groups were calculated by dividing the number of cancers observed by the total number of observation years. Each patient was counted once only, irrespective of how many synchronous can-cers the patient might have had as first cancan-cers. Later cancers were not considered. Cumulative incidence,
denoted by Q, was computed starting at age 25, assuming zero incidence before age 25, using the formula Q(age) = Q(age-1) + [1-Q(age-1)]·AIR(age) where AIR(age) is the annual incidence for the corresponding 5 year inter-val. The hazard rate H =−ln[1-AIR] was used with stand-ard error estimated as SEH = SEAIR/(1-AIR). The standstand-ard error, denoted by SEQ, was computed in two steps and 95% confidence intervals were estimated. Follow-up contin-ued after the occurrence of first cancers, and all patients were either reported to be alive or validated to be alive in a population register when censored. See our previous report [2] for a more detailed description of these methods. Differ-ences in time-to-events were also calculated by the Kaplan-Meier algorithm and Mantel-Cox p-values when appropriate.
Survival
Crude survival was calculated by the Kaplan-Meier algo-rithm and Mantel-Cox p-values as time from first cancer to last observation/death. Cancer stages at diagnosis and causes of death were not considered in this report.
Table 2 Studies assessing the effect of colonoscopy surveillance interval in LS
Study Ref. Subjects Inclusion criteria Setting CS Interval Findings
Järvinen, 2000 [3] 252 Amsterdam criteria and LS, gene tested
Prospective, controlled non-randomized trial
3 years CRC reduced 62% in 15 years compared to not screened.Mortality reduced 65% vs. no CS surveillance. Adherence 93%. Dove-Edwin, 2005 [13] 290 Amsterdam criteria Retrospective 3 years Estimated 72% reduction of CRC mortality
when screened. Adherence not reported. Mecklin, 2007 [4] 420 LS, gene tested Prospective, observational 3 years Estimated risk for CRC 22% for women and
35% for men before age 60. No increase in CRC mortality compared to non-carriers. Adherence 98%.
Järvinen, 2009 [14] 242 LS, gene tested Prospective, controlled non-randomized observational
3 years CRC incidence 12.4% in 11·5 years, no increase in CRC mortality compared to non-carriers. Adherence 96%. De vos tot Nederveen
Cappel, 2002
[15] 857 Amsterdam criteria or gene tested
Retrospective 2-3 years 10.5% cumulative CRC risk in 10 years under surveillance. Lower tumor stage if CS interval < 2 years.
Stormorken, 2007 [5] 601 Amsterdam criteria or gene tested
Prospective, observational 2-3 years CRC incidence of LS carriers not increased compared to non-carriers.
Adherence not reported. Newton, 2015 [6] 227 LS, gene tested Retrospective 2-3 years CRC incidence 25% at age 70.
Adherence 87%. Stupart, 2009 [16] 178 LS,MLH1 mutation Prospective, controlled
non-randomized observational
1-2 years CRC incidence 11% in 5 years compared to 27% if no surveillance.
Adherence not reported.
Vasen, 2010 [7] 745 LS, gene tested Retrospective 1-2 years CRC cumulative risk 6% in 7·2 years. Adherence not reported.
Engel, 2010 [17] 622 LS, gene tested Prospective, controlled non-randomized observational
1-2 years CRC cumulative risk at age 60 23%, early stages. Adherence 81% to 15 months. Stuckless, 2012 [18] 152 LS,MSH2 mutation Retrospective 1-2 years CRC reduced 71% in 10 years, interval
cancers 27% in males and 15% in females. Adherence 44%.
LS Lynch syndrome CRC colorectal cancer CS colonoscopy
Results
There were 7924 observation years in the final analysis from 430 males and 514 females (n = 944). The Finnish series included 4625 and the non-Finnish series 3299 observation years after first colonoscopies. Ages at inclu-sion were similar for both series (35.2 years and 36.1 years, respectively;p > 0.05). Baseline characteristics of the study population and the classification of path_MLH1 variants are presented in Table 3.
Classification ofpath_MLH1 variants
Seven hundred and six (75%) of the patients carried path_MLH1 variants found in LOVD, and 238 of vari-ants (25%) were not found in LOVD. Among the 706 found in LOVD, 691 (98%) were pathogenic (class 5) and 15 (2%) were probably pathogenic (class 4). Among the 505 in the Finnish series 406 (80%) and four (0.7%) had class 5 and class 4 variants, Among the non-Finnish series 285 (65%) had class 5 and 11 (2.5%) class 4 variants in LOVD, Among the 238 variants not reported to LOVD 95 were detected in the Finnish series and 143 in the non-Finnish series. All of them were eventually classified as class 5 and 4 based on the combined assess-ment of two of the co-authors (IF, JS) following the updated InSight rules [19].
Cumulative incidences of cancers
A total of 101 CRCs and 83 extra-colonic cancers were di-agnosed during the follow-up period. Despite less frequent colonoscopy, the cumulative incidences of CRC were mod-estly lower for the Finnish series compared to the non-Finnish series in all age groups (39.2%; 95% confidence interval 29.4–48.9 vs 53%; 39.6–68) but not significantly so. Regarding extra-colonic cancers, similar observations were made (39.7%; 28.2–51.2 vs 57.2%; 41–73.5, respectively). The cumulative incidence rates categorized by 10-year in-tervals from age 25 are shown in Table 4 and Fig. 1a and b. Additional file 1: Table S1 presents the annual incidence rates of cancers categorized by five-year intervals from 25 to 70 years.
The similar age of inclusion allowed us to make com-parisons of time from inclusion to diagnosis of CRC using the Kaplan-Meier algorithm. In the Finnish series,
3 and 11% of carriers were diagnosed with CRC after 5 and 10 years of follow-up, respectively, compared to 5 and 14%, respectively in the non-Finnish series (p > 0.05). The differences were modestly larger in males than in females (Fig. 1c). The percentages of carriers developing extra-colonic cancers were also similar: 3 and 9% at 5 and 10 years after inclusion in the Finnish series compared to 3 and 11% in the non-Finnish series (p > 0.05). In sum, none of the differences were signifi-cant and all point estimates were similar or lower in the Finnish series.
Correlation with population incidence of CRC
Next, we explored the correlation between observed CRC incidences inpath_MLH1 LS patients and the cor-responding population incidences of CRC. The relative incidence of CRC in the Finnish population compared to the other countries was 0.80 [the age-standardized inci-dence rate in Finland was 35.0 per 100,000 versus a mean of 43.6 per 100,000 for the other reporting coun-tries (http://eco.iarc.fr/EUCAN/; downloaded October 2015)]. By comparison, the observed ratio of cumulative risk for CRC at 70 years in the Finnish series of path_MLH1 carriers compared to the others was similar: 0.72 (39.2% in the Finnish series versus the average of 54.8% in other countries combined).
Time since last colonoscopy to CRC and survival
The mean time from last colonoscopy to CRC did not differ between the Finnish and non-Finnish series irre-spective of the interval between colonoscopies. It was 32.7 (SD 13.6) months for the Finnish series and 31.0 (SD 23.4) months for the non-Finnish series (p > 0.05). Times since last colonoscopy to CRC in the two series by 6 months periods are shown in Table 5. Of note, the rates of interval cancers occurring before the next planned 2-yearly or 3-yearly colonoscopy were similar in both series at 56.9% and 50% in the Finnish and the others respectively (Table 5).
Moreover, there were no differences in the survival of CRC inMLH1 carriers in the two series. Five- and ten-year overall survival after CRC was 90% (95% confidence interval: 78-96%) and 88% (75-95%), respectively, in the Finnish series compared to 96% (85-99%) and 91% (78-97%) in the 1-2-year interval series (p > 0.05). There were not enough deaths for meaningful stratification by time since last colon-oscopy with respect to survival. Finally, there were no differ-ences in survival of extracolonic cancers. Five- and ten-year survival after extra-colonic cancer was 79% (64-89%) and 79% (64-89%), respectively, in the Finnish series compared to 82% (68-92%) and 82% (69-92%) in the 1-2-year interval series (p > 0.05).
Table 3 Baseline characteristics of the study population
All subjects 3-year interval (Finnish) 1-2-year interval (non-Finnish) Observation years 7928 4625 3299 Number of subjects 944 505 439 Gender Male 430 246 (48.7%) 184 (41.9%) Female 514 259 (51.3%) 255 (58.1%) Age at inclusion (Mean, SD) 35.5 (11.7) 35.2 (12.1) 36.1 (11.0) Follow-up time (Mean, SD) 8.4 (5.7) 9.2 (5.9) 7.5 (5.2) SD standard deviation
Discussion
This study showed that the high incidence of CRC ob-served in our combined international series of path_MLH1 carriers was not caused by a higher inci-dence in the Finnish series compared to the others. In contrast to what we expected, the CRC incidence in the Finnish series was lower than in the others, but not sig-nificantly so.
First, we considered the possibility that the trend towards a lower CRC incidence in the Finnish series could reflect the lower population incidence of CRC in Finland. In fact, the observed ratio of cumulative risk for CRC at 70 years showed a similar pattern in the Finnish and non-Finnish series. Disease expression differences between Finnish and non-Finnish path_MLH1 carriers could reflect population-specific environmental and behavioural factors or a lower penetrance of the Finnish founder path_MLH1 variants compared to other path_MLH1 variants but this study shows that these factors cannot have a major impact on the observed high
cumulative risk of CRC in path_MLH1 carriers in the total PLSD cohort ofpath_MLH1 patients.
Secondly, we examined whether or not the Finnish patients were actually colonoscoped less frequently than the others. We found that the time between last colon-oscopy and CRC was similar for both series irrespective of the recommendations in place. Also, it was evident that a proportion of CRCs in both series could be classi-fied as interval cancers (Table 5). In particular, the rates of interval cancers that occurred before the planned next 2-yearly or 3-yearly colonoscopy were 56.9% and 50% in the Finnish series and the others, respectively (Table 5). While the organizational aspects of surveillance at the non-Finnish centers were heterogenous and details that might impact our observations were not readily avail-able, the organization of surveillance in the Finnish series displays two key features that are critical for the interpretation of our findings: there are special and dedi-cated booking and call back systems in place to follow all identified LS carriers and the reported adherence to
Table 4 Cumulative incidences from 25 years of age and 95% confidence intervals for colorectal cancer and extra-colonic cancer
3-year interval (Finnish) 1-2-year interval (non-Finnish)
Current age Age stop Obs years #Ca Cumulative incidence (%)
95% CI Obs years #Ca Cumulative
incidence (%) 95% CI Colorectal cancer All 25 40 1982 19 12.9 [7.4–18.3] 1299 17 16.4 [9.2–23.7] 25 50 3301 40 25.4 [18.6–32.3] 2424 36 30.0 [21.7–38.3] 25 60 4070 47 31.7 [24.0–39.4] 2935 48 44.9 [34.6–55.2] 25 70 4330 51 39.2 [29.4–48.9] 3094 50 53.8 [39.6–68.0] Male 25 40 1026 12 15.7 [7.5–23.9] 610 9 18.5 [7.2–29.7] 25 50 1682 25 30.8 [20.7–40.9] 1110 21 37.0 [24.3–49.8] 25 60 2075 29 36.9 [26.1–47.7] 1288 28 57.8 [41.5–74.0] 25 70 2189 30 41.1 [28.2–54.0] 1365 28 57.8 [41.5–74.0] Female 25 40 956 7 9.6 [2.8–16.4] 689 8 14.8 [5.3–24.4] 25 50 1623 15 19.4 [10.6–28.3] 1314 15 24.1 [13.4–34.8] 25 60 2010 18 26.2 [15.2–37.2] 1646 20 35.2 [22.0–48.3] 25 70 2156 21 36.4 [22.1–50.6] 1729 22 55.3 [30.5–80.0] Extra-colonic cancer All 25 40 1982 4 2.7 [0.1–5.3] 1299 3 2.9 [0.0–6.1] 25 50 3301 24 16.9 [10.7–23.2] 2424 22 17.8 [11.0–24.6] 25 60 4070 39 32.2 [23.5–40.9] 2934 35 35.3 [24.8–45.7] 25 70 4330 42 39.7 [28.2–51.2] 3094 41 57.2 [41.0–73.5]
Obs years observation years at age group #Ca number of cancers during observation CI confidence interval
colonoscopy intervals has been consistently very high throughout the years [4, 8]. Thus, in the Finnish series non-compliance/adherence with local surveillance guidelines cannot explain the occurrence of all cancers and the pattern of time from last colonoscopy to CRC suggests that only a limited proportion of CRCs would have been prevented by reducing the interval from 3 to 2 years.
Our study has a number of strengths including: (i) a large number of observation years; (ii) a focus on path_MLH1 carriers showing a high cumulative risk thereby avoiding mixing of carriers of path_MMR vari-ants in different MMR genes and (iii) the robustness of the dataset collated based upon prospectively observed outcomes. On the other hand, several limitations need to be highlighted: (i) in spite of the number of observa-tion years included our sample size is still limited. Sto-chastic variation cannot be completely ruled out and our observations do not exclude a significant impact of dif-ferences in population prevalence of CRC on LS expres-sivity; and (ii) only a detailed analysis of the interval, quality and reported findings of the colonoscopies will allow a refined assessment of the impact of this con-founder. However, such an analysis will not change the critical observation that time between colonoscopy and CRC is essentially the same in both series.
The prospective health outcome observations pre-sented here challenge the dogma that the performance of very frequent colonoscopies, many of them performed in expert centers, has a strong primary preventive effect on CRC incidence in LS. It is notable that despite sur-veillance, the expert centers with good recall systems in place that have contributed their data to this study have not succeeded in preventing CRC as has been achieved in non-LS familial CRC [20]. Consequently, our observa-tions set the foundaobserva-tions for a more detailed analysis of the determinants of this lack of success. In this regard, there is biological evidence that CRC in LS may arise directly without a precursor polyp although the relative contribution of this distinct natural history to the totality of CRCs observed is a matter of controversy [21–24]. Thus, it is possible that even colonoscopies achieving the best quality standards would not be able to prevent all CRCs in LS.
Fig. 1 a Calculated cumulative incidence for colorectal cancer in the 3-year and non-Finnish series. Fin = Finnish series (blue line). Oth = non-Finnish series (green line). b Calculated cumulative incidence for extra-colonic cancer in the 3-year and non-Finnish series. Fin = Finnish series (blue line). Oth = non-Finnish series (green line). c Calculated cumulative incidence for colorectal cancer by gender in the 3-year and non-Finnish series. Fin_M = Finnish series, males (blue line). Fin_F = Finnish series, females (red line).
Oth_M = non-Finnish series, males (green line). Oth_F = non-Finnish series, females (orange line)
Whether shorter colonoscopy interval could result in lower CRC stage needs to be addressed in future studies with cancer stage included. We are in the process of expanding our database in this regard.
Conclusions
In summary, we tested whether or not the high inci-dence of CRC in path_MLH1 carriers observed in our previous reports was caused by a distinct high incidence in the Finnish series in which 3-yearly colonoscopy was recommended. In the present report we show that the cumulative risk of CRC is high forpath_MLH1 carriers undergoing colonoscopic surveillance irrespective of the specific characteristics of their country of origin and the associated factors that may have an impact on the ex-pression of the disease. The contribution of more obser-vation years from countries with different population CRC incidences will be needed to formally test the hy-pothesis that population CRC incidence correlates with LS expression. The lack of a difference in the time be-tween last colonoscopy and CRC in the two series inves-tigated in this study challenges current beliefs regarding colonoscopy intervals in LS surveillance. Our findings mandate a detailed study that will eventually inform pol-icy makers. Finally, in view of the excellent 10-year over-all survival in the Finnish and non-Finnish series we remain strong advocates of current surveillance practices for those with LS pending studies that will inform new recommendations on the best surveillance interval.
Additional file
Additional file 1: Table S1. Annual incidence rates (AIR) and 95% confidence intervals for colorectal cancer and extra-colonic cancer. (DOCX 15 kb)
Abbreviations
AIR:Annual incidence rate; CI: Confidence interval; CRC: Colorectal cancer; ICD9: International Classification of Disease, 1975 revision.;
InSiGHT: International Society for Gastrointestinal Hereditary Tumours; LOVD: Leiden Open Variation Database; LS: Lynch Syndrome; MMR: Mismatch repair;path_MLH1: Pathogenic (disease-causing) variant of the MLH1 gene; path_MSH2: Pathogenic (disease-causing) variant of the MSH2 gene; path_MSH6: Pathogenic (disease-causing) variant of the MSH6 gene; path_PMS2: Pathogenic (disease-causing) variant of the PMS2 gene Acknowledgements
Not applicable. Funding
The Finnish contribution: The Finnish Cancer Foundation, The Sigrid Juselius Foundation, Mary and Georg C. Ehrnrooth foundation, Jane and Aatos Erkko foundation and State Research Funding. The Spanish contribution: Spanish Ministry of Economy and Competitiveness, the Carlos III Health Institute, the Scientific Foundation Asociación Española Contra el Cáncer and the Government of Catalonia. The Welsh Contribution: Wales Gene Park. The study sponsors did not have a role in planning the study design; in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. We have published a website www.lscarisk.org on which cancer risks for all published data can be reviewed and calculated in graphic form.
Authors’ contributions
TS, PM, GDE, JRS, GC, JB, GM and IMF wrote the paper. PM: Designed the study, managed the database and computed the results. EH, SN, EAR and KT calculated the confidence intervals to the cumulative incidences. All others: Participated in study design, interpreting of results, commenting on the manuscript and approved the final manuscript.
Ethics approval and consent to participate
All reporting centers obtained informed consent for genetic testing and surveillance procedures. De-identified data was exported for the current study. No named registry needing approval was established for the current study. Consent for publication
Not applicable. Competing interests
Toni Seppälä: a co-owner (20%) of Healthfund Finland Oy (educational and health care services in Finland, not related to patients or scope of this manuscript). Travel costs to a scientific meeting by Medtronic Finland. John Burn: a patent for high speed low cost tumor profiling pending to John Burn and QuantuMDx.
All others: None declared.
Table 5 Months since last colonoscopy with no cancer to colorectal cancer diagnosed
3-year interval (Finnish) 1-2-year interval (non-Finnish)
Months since last colonoscopy Number CRC Cumulative number CRC Cumulative % Number CRC Cumulative number CRC Cumulative %
<6 0 0 0% 0 0 0% 7–11 2 2 3.9% 5 5 10% 12–17 3 5 9.8% 13 18 36% 18–23 4 9 17.6% 7 25 50% 24–29 17 26 51% 6 31 62% 30–35 3 29 56.9% 4 35 70% 36–41 14 43 84.3% 3 37 74% 42–47 3 46 90.2% 3 40 80% 48–120 5 51 100% 10 50 100% CRC colorectal cancer
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Author details
1Department of Surgery, Helsinki University Hospital and University of
Helsinki, Post Box 340, 00029 Helsinki, Finland.2Finnish Lynch Syndrome
registry, Helsinki University Hospital, Helsinki, Finland.3Department of Education and Science, Central Finland Health Care District, Jyväskylä, Finland.4Manchester Centre for Genomic Medicine, Central Manchester
University Hospitals NHS Foundation Trust, Manchester, UK.5Manchester
Centre for Genomic Medicine, Institute of Human Development, MAHSC, University of Manchester, Manchester, UK.6Genome-Scale Biology Research
Program, University of Helsinki, Helsinki, Finland.7Danish HNPCC Register,
Hvidovre University Hospital, Copenhagen, Denmark.8Department Surgical
Gastroenterology, Aalborg University Hospital, Aalborg, Denmark.
9Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der
Universität München, Ziemssenstr. 1, 80336 Munich, Germany.10MGZ–
Medizinisch Genetisches Zentrum, Bayerstr. 3-5, 80335 Munich, Germany.
11
Unit of Hereditary Digestive Tract Tumors IRCCS Istituto Nazionale Tumori Milan, Milan, Italy.12Department of Molecular Medicine and Surgery,
Karolinska Institutet, Stockholm, Sweden.13Colorectal Medicine and Genetics,
The Royal Melbourne Hospital, Melbourne, Australia.14Department of
Medicine, Melbourne University, Melbourne, Australia.15Hereditary Cancer Program. Institut Català d’Oncologia-IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain.16Department of Genetics, University of Groningen,
University Medical Center Groningen, Groningen, the Netherlands.17Institute
of Medical Genetics, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK.18Department of Gastroenterology and Hepatology, Leiden
University Medical Centre, Leiden, the Netherlands.19Institute of Human
Genetics, Newcastle upon Tyne, UK.20Department of Tumor Biology, Institute
of Cancer Research, The Norwegian Radium Hospital, part of Oslo University Hospital, Oslo, Norway.21Institute of Cancer Genetics and Informatics, The
Norwegian Radium Hospital, part of Oslo University Hospital, Oslo, Norway.
22Department of Informatics, University of Oslo, Oslo, Norway.23Department
of Mathematics, University of Oslo, Blindern, Oslo, Norway.24Department of Gastroenterology and Hepatology, Isala Clinics, Zwolle, the Netherlands.
25Department of Surgery, Central Manchester University Hospitals NHS
Foundation Trust, Manchester, UK.26Department of Clinical Genetics and
Department of Human Genetics Leiden University Medical Centre, Leiden, The Netherlands.27Department of Clinical Genetics, Aarhus University
Hospital, Aarhus, Denmark.28Department of Biomedicine, Aarhus University,
Aarhus, Denmark.29Department of Women’s and Children’s health, Division
of Obstetrics and Gynecology, Karolinska Institutet, Karolinska University Hospital, Solna S171 76, Stockholm, Sweden.30Centre for Epidemiology and
Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, Australia.31Medical Genetics Unit,
University of Florence, Florence, Italy.32Center for Hereditary Tumors, HELIOS University Hospital Wuppertal, University Witten/Herdecke, Witten, Germany.
33Department für Humanmedizin, Universität Witten/Herdecke, Witten,
Germany.34University of Eastern Finland, Kuopio, Finland.35Research Group
Inherited Cancer, The Norwegian Radium Hospital, Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
Received: 8 June 2017 Accepted: 2 October 2017
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